The diverse cell types of the blood arise through sequential stages of commitment and differentiation from a single type of progenitor, the hematopoietic stem cell. During this process, cells progressively make irreversible cell type transitions, in which they maintain the potential to differentiate into some cell types, while losing the potential for others. Each transitions is determined by changes in transcription within each cell, such that genes required for the phenotype of the new, more-specialized cell type increase in transcriptional output, while those genes characteristic of other lineage branches are suppressed. The activity of every gene is controlled by a combination of inputs from transcription factors and the epigenetic state of the relevant genomic locus. Here, I propose to use a functional assay for epigenetic state, based on cell fusion and gene expression analysis, to dissect the role of epigenetic gene silencing in lineage-specific gene regulation, using the hematopoietic system as a model. Using this method, I will identify genes for which epigenetically silencing controls lineage commitment within the hematopoietic system. Further analysis will identify the precise mechanisms of epigenetic regulation responsible for silencing important hematopoietic genes. The results of these studies should expand our understanding of mechanisms regulating cell fate specification as it relates to development and disease, particularly within the hematopoietic system. Aberrant cell differentiation has been linked to numerous diseases, including cancer and immune disorders. Specifically, hematological malignancies, such as leukemia, lymphoma, and myeloma, are associated with improper differentiation of hematopoietic cells. A deeper understanding of the regulation of gene expression as it relates to the process of cell differentiation will greatly assist in the diagnosis, classification, and treatment of such disorders. Furthermore, the assays described here should serve as a foundation for further study of lineage-specific epigenetic effects.